The search for the genetic factors contributing to Alzheimer disease (AD) has evolved tremendously throughout the years. It started from the discovery of fully penetrant mutations in Amyloid ...precursor protein, Presenilin 1, and Presenilin 2 as a cause of autosomal dominant AD, the identification of the ɛ4 allele of Apolipoprotein E as a strong genetic risk factor for both early-onset and late-onset AD, and evolved to the more recent detection of at least 21 additional genetic risk loci for the genetically complex form of AD emerging from genome-wide association studies and massive parallel resequencing efforts. These advances in AD genetics are positioned in light of the current endeavor directing toward translational research and personalized treatment of AD. We discuss the current state of the art of AD genetics and address the implications and relevance of AD genetics in clinical diagnosis and risk prediction, distinguishing between monogenic and multifactorial AD. Furthermore, the potential and current limitations of molecular reclassification of AD to streamline clinical trials in drug development and biomarker studies are addressed.
Genetic insights in Alzheimer's disease Bettens, Karolien, PhD; Sleegers, Kristel, PhD; Van Broeckhoven, Christine, Prof
Lancet neurology,
2013, January 2013, 2013-Jan, 2013-01-00, 20130101, Volume:
12, Issue:
1
Journal Article
Peer reviewed
Summary In the search for new genes in Alzheimer's disease, classic linkage-based and candidate-gene-based association studies have been supplanted by exome sequencing, genome-wide sequencing (for ...mendelian forms of Alzheimer's disease), and genome-wide association studies (for non-mendelian forms). The identification of new susceptibility genes has opened new avenues for exploration of the underlying disease mechanisms. In addition to detecting novel risk factors in large samples, next-generation sequencing approaches can deliver novel insights with even small numbers of patients. The shift in focus towards translational studies and sequencing of individual patients places each patient's biomaterials as the central unit of genetic studies. The notional shift needed to make the patient central to genetic studies will necessitate strong collaboration and input from clinical neurologists.
Genome-wide association studies (GWAS) originally identified ATP-binding cassette, sub-family A, member 7 (
ABCA7
), as a novel risk gene of Alzheimer’s disease (AD). Since then, accumulating ...evidence from in vitro, in vivo, and human-based studies has corroborated and extended this association, promoting
ABCA7
as one of the most important risk genes of both early-onset and late-onset AD, harboring both common and rare risk variants with relatively large effect on AD risk. Within this review, we provide a comprehensive assessment of the literature on
ABCA7
, with a focus on AD-related human -omics studies (e.g. genomics, transcriptomics, and methylomics). In European and African American populations, indirect
ABCA7
GWAS associations are explained by expansion of an
ABCA7
variable number tandem repeat (VNTR), and a common premature termination codon (PTC) variant, respectively. Rare
ABCA7
PTC variants are strongly enriched in AD patients, and some of these have displayed inheritance patterns resembling autosomal dominant AD. In addition, rare missense variants are more frequent in AD patients than healthy controls, whereas a common
ABCA7
missense variant may protect from disease. Methylation at several CpG sites in the
ABCA7
locus is significantly associated with AD. Furthermore,
ABCA7
contains many different isoforms and
ABCA7
splicing has been shown to associate with AD. Besides associations with disease status, these genetic and epigenetic
ABCA7
markers also showed significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human-based –omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism, and future studies should make clear if interventions on
ABCA7
expression can serve as a valuable therapeutic target for AD.
Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of ...onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPα). These mutations—causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively—are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPα in neuronal cells. The resulting depletion of functional CSPα might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPα in humans and demonstrates the need for detailed investigation of CSPα in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation.
Abstract
Summary
Here we describe NanoPack, a set of tools developed for visualization and processing of long-read sequencing data from Oxford Nanopore Technologies and Pacific Biosciences.
...Availability and implementation
The NanoPack tools are written in Python3 and released under the GNU GPL3.0 License. The source code can be found at https://github.com/wdecoster/nanopack, together with links to separate scripts and their documentation. The scripts are compatible with Linux, Mac OS and the MS Windows 10 subsystem for Linux and are available as a graphical user interface, a web service at http://nanoplot.bioinf.be and command line tools.
Supplementary information
Supplementary data are available at Bioinformatics online.
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